title: Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase.
abstract: Administration of metformin is known to reduce both body weight and food intake. Although the hypothalamus is recognized as a critical regulator of energy balance and body weight, there is currently no evidence for an effect of metformin in the hypothalamus. Therefore, we sought to determine the central action of metformin on energy balance and body weight, as well as its potential involvement with key hypothalamic energy sensors, including adenosine monophosphate-activated protein kinase (AMPK) and S6 kinase (S6K). We used meal pattern analysis and a conditioned taste aversion (CTA) test and measured energy expenditure in C56BL/6 mice administered metformin (0, 7.5, 15, or 30 μg) into the third ventricle (I3V). Furthermore, we I3V-administered either control or metformin (30 μg) and compared the phosphorylation of AMPK and S6K in the mouse mediobasal hypothalamus. Compared with the control, I3V administration of metformin decreased body weight and food intake in a dose-dependent manner and did not result in CTA. Furthermore, the reduction in food intake induced by I3V administration of metformin was accomplished by decreases in both nocturnal meal size and number. Compared with the control, I3V administration of metformin significantly increased phosphorylation of S6K at Thr(389) and AMPK at Ser(485/491) in the mediobasal hypothalamus, while AMPK phosphorylation at Thr(172) was not significantly altered. Moreover, I3V rapamycin pretreatment restored the metformin-induced anorexia and weight loss. These results suggest that the reduction in food intake induced by the central administration of metformin in the mice may be mediated by activation of S6K pathway.
authors.affiliation: Department of Pharmacology, Korea University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Park
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Oh
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Park
authors.forename: Kyung-Ho
authors.initials: KH
authors.lastname: Shin
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Choi
authors.forename: Boe-Gwun
authors.initials: BG
authors.lastname: Chun
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001069:Appetite Regulation / Q000187:drug effects* / Q000502:physiology*; D004789:Enzyme Activation; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology*; D057967:Infusions, Intraventricular; D008297:Male; D062407:Meals / Q000187:drug effects* / Q000502:physiology*; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D019893:Ribosomal Protein S6 Kinases / Q000096:biosynthesis*; D020542:Third Ventricle / Q000187:drug effects / Q000502:physiology
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin; D019893:Ribosomal Protein S6 Kinases
keywords: AMP-activated protein kinase; S6 kinase; energy homeostasis; hypothalamus; meal pattern; metformin